A novel NR5A1 variant in an infant with elevated testosterone from an Australasian cohort of 46,XY patients with disorders of sex development.

Joyce Y Wu,Mark Harris,Lin Lin,Salim Aftimos,Kristen A Neville,Catherine S Choong,Ivan N Mcgown,Andrew M Cotterill,David M Cowley,John C Achermann

doi:10.1111/cen.12012

Abstract

BackgroundNR5A1 loss-of-function mutations are increasingly found to be the cause of 46,XY disorders of sex development (DSD).ObjectiveTo determine the presence of NR5A1 mutations in an Australasian cohort of 17 46,XY DSD patients with presumed androgen insensitivity syndrome (AIS) who were negative for androgen receptor gene (AR) mutation.DesignExons 2-7 of NR5A1 were PCR amplified and sequenced. Gene expression and cellular localization studies were performed on a novel NR5A1 variant c.74A>G (p.Y25C) identified in this study.ResultsWe identified one novel mutation, c.74A>G (p.Y25C) in a patient characterized by penoscrotal hypospadias with bifid scrotum. He had elevated testosterone and gonadotropins in early infancy. Functional analysis of p.Y25C in vitro demonstrated reduced transcriptional activation by SF-1 and partially impaired nuclear localization in a proportion of transfected human adrenal NCI-H295R cells.ConclusionThis is the first reported case of a DSD patient with a NR5A1 mutation and elevated testosterone levels. Our finding supports evaluation of NR5A1 mutations in 46,XY DSD patients with a range of testosterone levels.

Highlights

Disorders of sex development (DSD) encompass all the congenital conditions in which development of chromosomal, gonadal or anatomic sex is atypical
The detection rate for androgen receptor gene (AR) mutations in Complete androgen insensitivity syndrome (AIS) (CAIS) range from 66Á7% to 83%, whereas for Partial AIS (PAIS) patients, the detection rate for AR mutations range from 13Á6% to 28%
We evaluated the presence of NR5A1 mutations in an Australasian cohort of 17 46,XY DSD patients with presumed AIS who were negative for AR mutations

Summary

Introduction

Disorders of sex development (DSD) encompass all the congenital conditions in which development of chromosomal, gonadal or anatomic sex is atypical. Several investigators have reported heterozygous lossof-function mutations in the nuclear receptor subfamily five group A member 1 gene (NR5A1) in patients with clinical features of androgen insensitivity syndrome (AIS) but without androgen receptor gene (AR) mutations.[2] Mutations in AR, which is located on chromosome Xq11-q12, is responsible for AIS. The detection rate for AR mutations in Complete AIS (CAIS) range from 66Á7% to 83%, whereas for Partial AIS (PAIS) patients, the detection rate for AR mutations range from 13Á6% to 28%.3,4. AIS is characterized by a clinical spectrum ranging from phenotypically female patients (CAIS) to decreased virilization (PAIS) in 46,XY individuals with normal or elevated androgen levels.[5] The detection rate for AR mutations in Complete AIS (CAIS) range from 66Á7% to 83%, whereas for Partial AIS (PAIS) patients, the detection rate for AR mutations range from 13Á6% to 28%.3,4 AIS is characterized by a clinical spectrum ranging from phenotypically female patients (CAIS) to decreased virilization (PAIS) in 46,XY individuals with normal or elevated androgen levels.[5]

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